PROJECT SUMMARY Hepatitis C virus (HCV) and HIV are two chronic viral pathogens that disproportionately affect people of racial, gender, and socioeconomic minorities. The proposed studies aim to use a multi-pronged approach to study HCV, HIV and their co-infection, with epidemiologic, clinical, and basic science components. To study HCV coinfection in HIV-infected individuals, we have established a cohort of 1985 HIV-infected men receiving care at a multisite community health center in Metropolitan Baltimore. The study cohort encompasses various underrepresented minority groups. A large database with >85 variables has been built and quality-verified based on these patients. We have studied HCV incidence in this cohort and found a resurgence of incident HCV among men who have sex with men (MSM) since 2010, which was associated with polydrug use and co- occurrence of other sexually transmitted infections (STIs). One aim of this project is to perform further analyses using the existing database to achieve more discoveries and publishable findings. We propose to analyze the trends and risk factors of prevalent HCV, chronic HCV cascade of care and treatment uptake, and factors associated with spontaneous HCV clearance among the HIV-infected men. We will also analyze the syndemic of HCV, other STIs, and polydrug use among the HIV-infected MSM. Some minorities, such as African American MSM, transgender women, and residents of certain zip codes will be studied separately. The other aim of the project is to employ a unique model system of long-term culture (> 3 months) of primary human macrophages developed in our lab to study HIV latency and reactivation in these cellular reservoirs. Tissue macrophages have recently been shown to be the major ?sanctuary? for HIV in the presence of antiretroviral treatment. Thus, a consistent and stable ex vivo and in vitro model to study long-term interactions between HIV and macrophages will be of great utility in the effort toward an HIV cure. In addition, HIV-induced chronic inflammation remains elevated in patients with undetectable viremia. Thus, we will test the hypothesis that macrophage reservoirs persistently infected with HIV play a role in enhancing and sustaining HIV-induced chronic immune activation through viral relapse and/or secreting virally modified exosomes. The results from this project will have important impact on the public health effort toward the eradication of these two important viral pathogens. 1